PROJECT SUMMARY/ABSTRACT The goal of this R01 proposal is to probe deeply into the regulatory processes that underlie biological diversity within brain tissue samples from individuals free of psychiatric disorder and individuals with bipolar disorder, schizophrenia, or major depressive disorder. This proposal combines unique experimental and analytical innovations and a high-quality data production pipeline. High-quality dissected tissue from 9 anatomical sub- regions from each of 4 post-mortem human brains free of psychiatric disease will be analyzed, along with neuronal cell lines from 4 individuals collected by PsychENCODE investigators. Genome-wide binding profiles from ?ChIP-seq? experiments for 100 transcription factors will be measured across these tissue and cell types. In addition, 6 of the key transcription factors will be analyzed in 2 brain regions from 96 individuals, including individuals that were free of psychiatric disease (n=24) or had bipolar disorder (n=24), schizophrenia (n=24), or major depressive disorder (n=24. These data will be used to assess the hypothesis that differential transcription factor activity contributes directly to the risk and manifestation of disease, and is motivated by previous observations from our groups of disease-associated transcriptional changes in brain tissue. Further, integrative analyses of all these data, along with measurements of transcripts, DNA methylation, and other data types that will be generated, will greatly enhance our understanding of the functional variability between people and across different brain regions within a given person. These data will furthermore result in the characterization of differences between healthy and disorder-affected individuals that may point to genes and pathways that are of special diagnostic, prognostic, or therapeutic value. Finally, these data will be shared to the greatest extent possible to substantially expand the depth and quality of brain tissue data resources accessible to the broader research community to reduce the medical burden of psychiatric disorders.